Protocol for paracentesis

ABSTRACT

The present invention relates to an improved method for the treatment of hypovolaemia or hypotension associated with therapeutic paracentesis, which method is characterised by the use of a peptide according to general formulae (I) or a salt thereof, wherin Asn, Cys, Gln, Gly, Phe and Pro represent the amino acid residues asparigine, cysteine, glutamine, glycine, phenylalanine and proline respectively; Phe(X) represents a phenylalanine residue optionally substituted at the 4-position of the aromatic ring by a group selected from methyl, ethyl, hydroxy and methoxy; Y represents a group —(CH 2 ) a —NH-Q, where a is 2–5 and Q is H or C(═NH)NH 2 ; and R represents a chain of between two and for αalpha-amino acid residues, at least one of which is glycine, as the active agent. The invention also provides uses of the peptide and pharmaceutical compositions.

The present invention relates to an improved method for the managementof ascites in cirrhotic individuals, and specifically for the control ofhypotension following paracentesis.

BACKGROUND

Cirrhosis of the liver is a common consequence of excessive alcoholconsumption or hepatitis. In about 30% of cases of cirrhosis there is abuild up of fluid in the peritoneal cavity. This is usually controlledby paracentesis. This procedure is frequently complicated byhypovolaemia and a fall in arterial blood pressure. The usual method forcontrolling this undesirable side effect is to administer an infusion ofhuman albumin. However, because human albumin is derived from donatedhuman blood, there is a risk that pathogens may be transmitted duringthe treatment. There is also a financial consideration. Even though itis sourced from voluntary donations in many countries, human albumin isexpensive, and paracentesis is generally repeated on a biweekly basisfor up to two years (depending on the availability of a suitable liverfor transplantation).

Overall then, there exists a need for a better method for the control ofhypotension following paracentesis. To reduce the risk of infection themethod should not involve the use of a product of human origin, andpreferably the cost of the treatment should be reduced.

BRIEF DESCRIPTION OF THE INVENTION

We have now found that terlipressin, a synthetic peptide previously usedin the control of bleeding oesophagal varices, can be used in place ofhuman albumin for the control of hypotension following paracentesis.Because terlipressin is a product of chemical synthesis it is notassociated with any risk of contamination by human pathogens. The use ofterlipressin in place of human albumin gives an equivalent clinicaloutcome, and the cost of the treatment is reduced. Furthermore, becauseterlipressin can be administered as a bolus injection rather than theinfusion required for albumin, the protocol is more convenient for thepatent.

The present invention therefore comprises, in a first aspect, animproved method for the control of hypotension following paracentesis,particularly in cases of cirrhosis of the liver.

In a second aspect, the present invention comprises a new use forterlipressin, which use is as an agent for the control of hypotensionfollowing paracentesis. In a third aspect, the invention comprises apharmaceutical composition for the control of hypotension followingparacentesis, which composition is a solution of terlipressin forinfusion.

Certain analogues of terlipressin may be considered as being equivalentto terlipressin for the purposes of the present invention.

DETAILED DESCRIPTION OF THE INVENTION

In a first aspect, the present invention comprises an improved methodfor the control of hypovolaemic hypotension associated withparacentesis. The method is characterised in that the therapeutic agentused to control the hypotension is terlipressin, or an analogue thereof.Suitable analogues are disclosed in U.S. Pat. No. 3,558,590 and itsequivalents (such as French Patent No. 1,492,017, UK Patent No.1,106,536, German Patent No. 1 493 561). They are described by generalformula 1:

wherein Cys, Phe, Gin, Asn, Pro and Gly represent the amino add residuescysteine, phenylatamine, glutamine, asparigine, proline and glycinerespectively, Phe(X) represents a phenylalanine residue optionallysubstituted at the 4-position of the aromatic ring by a group selectedfrom methyl, ethyl, hydroxy and methoxy, Y represents a chain of betweentwo and five methylene groups with a basic group such as amino orguanidino on the terminal methylene group, and R represents a chain ofbetween two and four α-amino acid residues, at least one of which isglycine.

Preferably, the peptide is Terlipressin, which is a compound accordingto general formula 1 in which R represents Gly-Gly-Gly; Phe(X)represents tyrosine; and Y represents (CH₂)₄NH₂.

Terlipressin, also known as GLYPRESSIN® or triglycyl lysine vasopressin,is a synthetic peptide. It is an analogue of vasopressin, which is anendogenous vasoactive hormone. Terlipressin is currently approved as ahaemostatic agent for the treatment of bleeding oesophagal varices.

Due to its chemical nature, terlipressin is capable of forming saltswith acids such as acetic acid and hydrochloric acid. All references toterlipressin in this document should be considered to include both thefree base and all such salts, and apply particularly to the acetate saltthat is the form actually marketed.

In a preferred embodiment, the paracentesis is required to relieveascites due to cirrhosis of the liver. While no causative factors areexcluded, the method is particularly applicable to cases of cirrhosisdue to excessive alcohol consumption or to hepatitis (includinghepatitis B and hepatitis C).

In another preferred embodiment, the terlipressin is administered byintravenous injection. A course of treatment may involve a singleinjection, or repeated injections. Preferably, the course of treatmentcomprises an injection immediately before the start of the paracentesisand one or more (such as two or three) injections following theparacentesis. A particularly preferred course of treatment comprises oneinjection prior to paracentesis and two injections afterwards. Theinjections may be separated by a period of a few hours, such as a periodof between 4 and 12 hours, more preferably between 6 and 10 hours. Amost preferred course of treatment comprises an injection before the,start of the paracentesis and follow-up injections 8 and 16 hours later.

The amount of terlipressin to be administered will be determined by theresponsible physician, taking into consideration all the relevantfactors. In a preferred embodiment of the invention, the amount ofterlipressin administered in each injection is between 0.1 mg and 10 mg.More preferably it is between 0.2 mg and 5 mg, and most preferablybetween 0.5 mg and 2 mg.

In a second aspect, the present invention comprises a new medical usefor the known therapeutic agent that is terlipressin. This new use is asan agent for the treatment of hypovolaemic hypotension due toparacentesis, particularly where the paracentesis is necessary to treatascites in a person suffering from cirrhosis of the liver.

In a preferred embodiment, the cirrhosis is a consequence of excessivealcohol consumption or hepatitis.

In another preferred embodiment, the terlipressin is administered byintravenous injection. More preferably, it is administered in more thanone intravenous injection. Most preferably, it is administered by anintravenous injection before the start of the paracentesis and twofurther injections after the paracentesis.

In a further preferred embodiment, the injections of terlipressin areseparated by a period of a few hours, such as a period of between 4 and12 hours, more preferably between 6 and 10 hours, most preferably aperiod of 8 hours.

In another preferred embodiment, the amount of terlipressin administeredis between 0.1 mg and 10 mg per injection, more preferably between 0.2mg and 5 mg, most preferably between 0.5 mg and 2 mg.

In a third aspect, the present invention comprises a pharmaceuticalcomposition for the treatment of hypovolaemic hypotension due toparacentesis, particularly paracentesis to treat ascites due tocirrhosis of the liver. The composition is characterised in that theactive pharmaceutical agent is terlipressin. The composition may furthercomprise such pharmaceutically acceptable agents as are known in theart. Such agents may include preservatives, bulking agents, solvents andthe like.

In a preferred embodiment, the composition is intended for intravenousinjection and so comprises a solvent. A preferred solvent is water, suchas pyrogen-free water for injection according the European Pharmacopeia.Another preferred solvent is isotonic saline. The composition may bepresented as a pre-prepared solution ready for use. Alternatively it maybe presented as a kit comprising a vial or other suitable vesselcontaining a measured quantity of terlipressin and another vialcontaining the solvent, such that the solution of terlipressin can beprepared immediately prior to use.

The foregoing description of the present invention is furtherillustrated in the following Example. The Example describes a clinicalstudy in which terlipressin and human albumin were compared directly.The protocol described should not be considered to be limiting as to thescope of the present invention.

EXAMPLE Comparison of the Effect of Terlipressin and Albumin in PatientsTreated by Paracentesis

Patient selection criteria: 24 clinically stable cirrhotic patients withtense ascites in need of therapeutic paracentesis were recruited to thestudy. Four were subsequently excluded prior to treatment. Patients wererandomly allocated to either the terlipressin or the albumin treatmentgroup. Useful data was obtained for 10 patients in each group. Table 1summarises the clinically relevant characteristics of the two groups.

TABLE 1 Characteristics of two treatment groups Terlipressin group (n =10) Albumin group (n = 10) Age (years) 50 ± 2 58 ± 2 Sex (M/F) 8/2 8/2Alcoholic cirrhosis 8 8 Beta blockers 3 3 Bilirubinaemia (μmol/L)  44 ±13 39 ± 5 Albuminaemia (g/L) 28.4 ± 2.0 29.6 ± 2.0 PT (%) 58 ± 5 49 ± 3Pugh score  9.4 ± 0.5  9.6 ± 0.2 Pugh grade B 6 6 C 4 4

Treatment: Both groups received therapeutic paracentesis according tothe usual protocol of the study centre. One group received 20% humanalbumin at a dose of 8 g per liter of removed ascitic fluid. The othergroup received 1 mg of terlipressin GLYPRESSIN® (triglycyl lysinevasopressin), Laboratoire F ring. Gentilly, France) as an intravenousbolus injection prior to paracentesis, and further 1 mg injections 8 and16 hours later (total dose 3 mg). Plasma renin and aldosterone levelswere measured as markers of blood volume. Certain other parameters weredetermined as secondary criteria for successful treatment. The resultsare summarised in Table 2.

TABLE 2 Results of treatment Terlipressin group (n = 10) Albumin group(n = 10) Removed ascitic fluid volume 6 ± 1 5 ± 1 (L) Period betweenparacentesis 5.5 ± 0.2 5.3 ± 0.3 treatment and discharge from hospital(days) Survival at 3 months (%) 86 89 Before 4–6 days later Before 4–6days later Reninaemia (pg/mL) 156 ± 81 130 ± 34 194 ± 47 223 ± 74Aldosteronaemia (pg/mL) 1017 ± 278 1337 ± 280 1149 ± 324 1420 ± 292Weight (kg) 77 ± 4 73 ± 3 72 ± 5 69 ± 4 Blood pressure (mmHg) 79 ± 3 78± 3 81 ± 4 79 ± 3 Creatininaemia 75 ± 9 72 ± 8 74 ± 4 71 ± 6 Natraemia(mmol/L) 134 ± 1  133 ± 1  134 ± 1  132 ± 1 

It is apparent from the above results that terlipressin and albumin areequally effective in treating hypovolaemia (as indicated by the valuesfor reninaemia and aldosteronaemia). Other parameters, including time todischarge from hospital and medium term survival are also comparable.The conclusion drawn is that terlipressin treatment is a validalternative to the use of human albumin in the control of hypovolaemichypotension following paracentesis. Furthermore, the use of terlipressineliminates the risk of infection associated with the use of atherapeutic agent derived from human blood, and the cost of treatment isreduced. In the study described in the Example above, the cost pertreatment with terlipressin was

990, compared to a cost per treatment with albumin of

1100. Finally, since terlipressin can be administered as a bolusinjection while albumin is administered by infusion, the protocol ismore convenient for the patient and the medical staff involved.

1. A method for the treatment of hypovolaemia or hypotension in asubject in need thereof following or during therapeutic paracentesis,comprising administering a peptide according to the general formulae 1or a salt thereof to said subject following or during therapeuticparacentesis,

wherein: Asn, Cys, Gln, Gly, Phe and Pro represent the amino acidresidues asparigine, cysteine, glutamine, glycine, phenylalanine andproline respectively; Phe (X) represents a phenylalanine residueoptionally substituted at the 4-position of the aromatic ring by a groupselected from methyl, ethyl, hydroxy and methoxy; Y represents a group—(CH2)_(a)—NH-Q, where a ranges from 2–5 inclusive and Q is H or C(═NH)NH₂; and R represents a chain of between two and four α-amino acidresidues, at least one of which is glycine, as the active agent.
 2. Amethod according to claim 1, wherein the peptide is terlipressin, or asalt thereof, as the active agent.
 3. A method according to claim 1,wherein the therapeutic paracentesis is necessary to relieve ascitesresulting from cirrhosis of the liver.
 4. A method according to claim 3,wherein the cirrhosis of the liver is a result of excessive alcoholconsumption or hepatitis.
 5. A method according to claim 2 wherein theterlipressin is administered by intravenous injection.
 6. A methodaccording to claim 5 wherein the terlipressin as administered as asingle injection prior to the start of the paracentesis and one or moreinjections after the paracentesis.
 7. A method according to claim 6wherein the terlipressin is administered as a single injection prior tothe start of the paracentesis and two injections after the paracentesis.8. A method according to claim 6 wherein the injections are separated byan interval of between 4 and 12 hours.
 9. A method according to claim 6wherein the injections are separated by an interval of between 6 and 10hours.
 10. A method according to claim 6 wherein the injections areseparated by an interval of approximately 8 hours.
 11. A methodaccording to claim 2 wherein the amount of terlipressin given at eachadministration is between 0.1 mg and 10 mg.
 12. A method according toclaim 2 wherein the amount of terlipressin given at each administrationis between 0.2 mg and 5 mg.
 13. A method according to claim 2 whereinthe amount of terlipressin given at each administration if between 0.5mg and 2 mg.